There has been a great deal of interest in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) over the past several years particularly related to the role of these molecules in cancer biology. MMPs are responsible for the invasion of tumors into normal tissue, tumor angiogenesis, and metastasis. There is a large body of research directed at finding MMP antagonists for the treatment of cancer (see e.g. Wojtowicz-Praga, et al., xe2x80x9cMatrix metalloproteinase inhibitors,xe2x80x9d Invest New Drugs, Vol. 15(1):61-75, 1997).
TIMP-3 is a member of a family of natural proteins which inhibit the activities of MMPs. There are at least 15 distinct MMPs with differing, but often overlapping, specificities which are responsible for degrading extracellular matrix molecules and breaking down (turning-over) the extracellular matrix of tissues and cells. TIMPs help to regulate the activity of MMPs and thereby control the extracellular matrix environment.
There are a variety of diseases and conditions that cause neovascularization in the eye which results in the loss of vision. One rate limiting step in the neovascular process is the breakdown of the basement membrane enclosing vascular endothelial cells which allows the vascular endothelial cells to migrate towards the angiogenic signal, proliferate, and form new capillaries. MMPs are responsible for this initial step in neovascularization, and a therapy directed towards inhibiting these MMPs would be angiostatic. TIMP-3 is a xe2x80x9cnaturalxe2x80x9d angiostatic agent which is made by retinal pigment epithelial cells (Della, et al., xe2x80x9cLocalization of TIMP-3 mRNA Expression to the Retinal Pigment Epithelium,xe2x80x9d Invest. Ophthal. and Visual Science, Vol. 37(9):1921-22, August, 1996; Ruiz, et al., xe2x80x9cTIMP-3 is Expressed in the Human Retinal Pigment Epithelium,xe2x80x9d Biochemical and Biophysical Res. Comm., Vol. 226(2):467-474, 1996) and resides in Bruch""s membrane between the choroid and retinal pigment epithelium (Vranka, et al., xe2x80x9cDiscrete Expression and Distribution Pattern of TIMP-3 in the Human Retina and Choroid,xe2x80x9d Current Eye Research, pg. 102-109, 1996; Fariss, et al., xe2x80x9cTissue Inhibitor of Metalloproteinases-3 Is a Component of Bruch""s Membrane of the Eye,xe2x80x9d American Journal of Pathology, Vol. 150(1):323-326, January, 1997) effectively providing an angiostatic barrier to the choroid. TIMP-3 has been shown to have angiostatic activity in vitro (Anand-Apte, et al., xe2x80x9cInhibition of Angiogenesis by Tissue Inhibitor of Metalloproteinase-3,xe2x80x9d Invest. Ophthal. and Visual Science, Vol. 38(5):817-821, April, 1997). Mutations in TIMP-3 are responsible for an inherited condition, Sorsby""s fundus dystrophy (Weber, et al., xe2x80x9cMutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby""s fundus dystrophy,xe2x80x9d Nature Genetics, Vol. 8:352-356, 1994; Felbor, et al., xe2x80x9cEvaluation of the Gene Encoding the Tissue Inhibitor of Metalloproteinases-3 in Various Maculopathies,xe2x80x9d Invest. Ophthal. and Visual Science, Vol. 38(6):1054-1059, May, 1997), which is characterized by subretinal neovascularization and hemorrhage and is clinically similar to the wet form of age-related macular degeneration (ARMD).
Diabetic retinopathy is currently treated with panretinal photocoagulation which destroys healthy retinal tissue to inhibit further neovascularization. Sub-foveal and juxtafoveal neovascular membranes in ARMD are treated with laser photocoagulation which causes an immediate vision loss in attempt to prevent further growth of the neovascular membrane. There are currently no effective therapies which inhibit ocular neovascularization without also causing the destruction of healthy tissue. The proposed invention would provide a method of inhibiting the neovascular disease process at an initial step in the neovascularization pathway.
The present invention is directed do compositions and methods for treating conditions associated with ocular neovascularization, specifically, corneal neovascularization, rubeosis iridis, neovascular glaucoma, age-related macular degeneration, diabetic retinopathy, ischemic retinopathy, and retinopathy of prematurity.